DESCRIPTION This project focuses on fatigue, an extremely common yet poorly understood complaint in patients affected by multiple sclerosis (MS). Primary fatigue, is fatigue not secondary to other MS-associated symptoms (e.g., sleep disorder or depression), is a distinct clinical entity and a cause of severe disability in most patients. A s fatigue limits everyday activities and it interfers with exercise-based rehabilitation, understanding its mechanisms is crucial to improving function and quality of life of Veterans with MS. Primary fatigue is divided in two broad categories, mental (cognitive) and physical (motor) fatigue, the latter being the focus of this proposal. Evidence suggests that primary motor fatigue originates within the central nervous system (CNS) but, although several factors have been invoked (e.g., demyelination, axonal loss, inflammation), a neurophysiological model to explain its underlying mechanisms is still lacking. First, with this project, we propose a characteristic eye movement abnormality, internuclear ophthalmoparesis (INO), as a simple and accessible model for primary motor fatigue in MS. INO is a disorder of binocular coordination (conjugacy), in which fast eye movements (saccades) of the adducting eye (i.e., the eye moving towards the nose) are slow during horizontal gaze shifts, due to demyelination of a specific CNS pathway (the medial longitudinal fasciculus, MLF). Preliminary results in a small MS group of patients show that patients with INO exhibit changes in ocular conjugacy (i.e., ocular motor fatigue) during a 10-minute saccadic fatigue test, but normal subjects do not. We hypothesize that ocular motor fatigue is representative of a major component of primary motor fatigue in MS, as it likely reflects deterioration of neural conduction fidelity along the demyelinated MLF axons. We aim at showing that ocular motor fatigue occurs in a larger MS population with INO by measuring changes of binocular conjugacy on eye movement recordings using two main measures: 1) abducting/adducting eye ratio for saccadic peak velocity (pulse size ratio); 2) time difference in occurrence of peak acceleration in the adducting vs. the abducting eye (pulse time delay), during the 10-minute fatigue test. We will determine whether ocular motor fatigue is associated with symptomatic subjective fatigue as assessed with standard fatigue questionnaires. Second, we intend to test efficacy of dalfampridine, a potassium channel blocker that enhances neural conduction along demyelinated axons, in MS patients with INO with or without associated ocular motor fatigue. Visual dysfunction in MS patients with INO is a major cause of disability as they are severely limited in daily activities such as driving and can suffer further disability when developing ocular motor fatigue during a sustained visual task (e.g., reading). However, no medical therapy is available for INO/ocular motor fatigue. Our preliminary results document improved binocular conjugacy in three MS patients taking dalfampridine for gait impairment (the FDA-approved indication for this medication). Our data also showed improvement of ocular motor fatigue after dalfampridine in one patient. We hypothesize that dalfampridine improves visual performance in MS patients with INO and counteracts ocular motor fatigue and, in turn, diminishes visual disability and improves quality of life. Thus, we will conduct a randomized, placebo-controlled, double-blind, crossover trial of dalfampridine (10mg twice a day) of 9 weeks duration. Before and after treatment, we will assess for changes in binocular conjugacy by eye movement measures as above, as well as changes in clinical measures, such as reading acuity and speed, saccades performance, gait performance, symptomatic fatigue, visual disability and quality of life. We will determine whether improvement of visual performance has positive effects on overall disability and quality of life of MS patients with INO. We will also determine whether there is an association between response of eye movement and gait performances to dalfampridine.